Field of the Invention
The present invention relates to the technical field of crystallization in pharmaceutical chemistry. Specifically, the present invention relates to novel solid forms of Afatinib monomaleate and preparation methods, pharmaceutical compositions and uses thereof.
Background
The chemical name of Afatinib is N-[4-(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide. It is also called BIBW 2992. The molecular formula is C24H25ClFN5O3 and the chemical structural formula is shown below:

Afatinib was developed by Boehringer Ingelheim Pharmaceuticals, Inc. Afatinib was approved by U.S. Food and Drug Administration and the European Medicines Agency in 2013, used in treating patients with EGFR mutated terminal or metastatic non-small cell lung cancer (NSCLC). The approved dosages are oral tablets. Afatinib is a powerful and selective dual irreversible epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases inhibitor.
Patent document WO2002/50043A1 disclosed the compound of Afatinib. Patent documents WO2007/054550A1 and WO2007/054551A1 disclosed indications of Afatinib.
Patent document WO2005/037824A2 (corresponding to patent document CN1867564B) disclosed a preparation method of crystalline form of Afatinib dimaleate. For convenience purpose, in the present invention, the Afatinib dimaleate described in WO2005/037824A2 is designated as “the crystalline form of Afatinib dimaleate in the prior art”
Patent document WO2009/147238A1 disclosed that Afatinib dimaleate described in WO2005/037824A2 has a fine needle-like morphology, which may lead to problems such as significant variations in bulk density and flowability issues due to orientation of needle-like particles, also may lead to capping or stacking, poor compressibility and API surface adhesion caused by increased electrostatic charge during the direct-compression processes of the tablets. The present inventors also found the solubility of the crystalline form of Afatinib dimaleate in the prior art is lower.
WO2012/121764A1 disclosed Form B of Afatinib dimaleate.
WO2013/052157A1 disclosed Forms C, D, E of Afatinib dimaleate. The researches by the present inventors showed that the Forms B, C, D, E of Afatinib dimaleate have serious hygroscopicity issues and are not suitable for storage and formulation application.
Patent document WO2012/121764A1 also disclosed various Afatinib acid addition salts and their crystalline forms, for example, Afatinib salts formed by Afatinib free base with one or more HmX wherein m is natural number, X is an anion of a pharmaceutically acceptable acid such as maleate, fumarate and so on. It also disclosed amorphous form of Afatinib diphenyl sulfonate salt, crystalline form of Afatinib fumarate salt, crystalline form of Afatinib disulphate salt, crystalline form of Afatinib dihydrochloride salt, crystalline form of Afatinib dioxalate salt, crystalline form of Afatinib dimesylate salt, crystalline form of Afatinib diphosphate salt, amorphous form of Afatinib di-L-malate salt, amorphous form of Afatinib citrate salt, crystalline form of Afatinib disuccinate salt, crystalline form of Afatinib di-L-aspartate salt, crystalline form of Afatinib difumarate salt. The patent document only generally mentioned that the above Afatinib acid addition salts and their crystalline forms have at least one beneficial property, but for any one of the above Afatinib acid addition salts or their crystalline forms, the patent document provided neither the kinds of beneficial properties nor test data relating to the beneficial properties and comparative data for practical applications.
Therefore, there is a need of developing Afatinib acid addition salts and their crystalline forms with more superior properties.